DISTINCT HUMAN MACROPHAGE RECEPTOR FOR ABNORMAL VLDL

描述：(改编自《调查员摘要》)： 巨噬细胞来源的泡沫细胞聚集在动脉粥样硬化病变和 以某些形式的高甘油三酯血症(HTG)存在于全身。吸纳 巨噬细胞异常富含甘油三酯脂蛋白(AbTGRLP) 受体(R)与低密度脂蛋白受体和乙酰低密度脂蛋白受体不同， 最近在小鼠巨噬细胞和人类中描述的研究人员 单核巨噬细胞可能参与HTG泡沫细胞的形成 人类。此外，该R还与氧化型低密度脂蛋白高亲和力结合， 提示这一途径可能在泡沫细胞的形成中起重要作用。 高胆固醇血症以及HTG。拟议工作的目标是 (1)人单核巨噬细胞受体的分离和鉴定 异常TGRLP和(2)鉴定存在于 在TGRLP中不存在或被掩盖的TGRLP对正常受试者和TO 确定降低HTG受试者的血浆甘油三酯水平是否使 TGRLP。人单核细胞系THP-1将被用作 可能的质膜结合蛋白的纯化 用于部分微测序和生产的候选受体 针对受体的抗体。分子生物学方法将 鉴定受体互补DNA克隆以阐明受体初级 结构，并对细胞内的mRNA进行鉴定。竞争性和直接性细胞 天然和修饰极低密度脂蛋白模型的结合和配体印迹研究 极低密度脂蛋白和定位的抗载脂蛋白B的单抗将识别结合 决定因素。这些研究应该提供基本的细胞和分子 与人类泡沫细胞形成有关的机制。

DESCRIPTION: (Adapted from the Investigator's abstract): Macrophage-derived foam cells accumulate in atherosclerotic lesions and throughout the body in some forms of hypertriglyceridemia (HTG). Uptake of abnormal triglyceride-rich lipoproteins (abTGRLP) by a macrophage receptor(R) distinct from the LDL R and the acetyl LDL R that the investigators recently described in murine macrophages and human monocyte-macrophages may be responsible for foam cell formation in HTG humans. Moreover, this R also binds oxidized LDL with high affinity, suggesting that this pathway may be important in foam cell formation in hypercholesterolemia as well as in HTG. The goals of the proposed work are (1) to isolate and characterize the human monocyte-macrophage receptor for abnormal TGRLP and (2) to identify the binding determinants present in abTGRLP that are absent or masked in TGRLP from normal subjects and to determine if lowering plasma TG levels in HTG subjects normalizes the TGRLP. The human monocytic line THP-1 will be used as a source for purification of plasma membrane binding proteins identified as likely receptor candidates for partial microsequencing and production of antibodies against the receptor. Molecular biological approaches will identify receptor complementary DNA clones to elucidate receptor primary structure and to characterize cellular mRNA. Competitive and direct cell binding and ligand blotting studies with native and modified VLDL, model VLDL, and mapped monoclonal antibodies against apoB will identify binding determinants. These studies should provide basic cellular and molecular mechanisms pertinent to foam cell formation in humans.